Abstract: The goal of the proposed research is to develop novel radiolabeled ultrasmall core shell nanoparticles (C' dots) decorated with alpha melanocyte stimulating hormone peptide analogs (DOTA-?MSH) that target the melanocortin-1 receptor (MC1-R) overexpressed on melanoma cells for targeted radiotherapy. The DOTA-?MSH-C' dots will be radiolabeled with the beta particle emitter 177Lu and the alpha emitter 225Ac. Upon binding, the radiolabeled DOTA-?MSH-C' dots are internalized into the melanoma cells sequestering the radionuclide within the cell near the nucleus for optimal radiation deposition. This approach is innovative because the nanoplatform transforms the properties of the individual components, such as the melanoma avid ?MSH peptide's MC1-R affinity and the pharmacokinetics of the conjugated radionuclides, to yield an ultrasmall nanoparticle with superior melanoma targeting and in vivo therapeutic properties. The central hypothesis is that C' dot nanoparticle targeted therapy with alpha 225Ac and beta 177Lu emitting radionuclides will result in efficacious melanoma treatment due to optimal melanoma tumor targeting and irradiation coupled with rapid in vivo clearance kinetics. Preliminary data supports the hypothesis and shows that the DOTA- ?MSH-C' dots have superior affinity and in vivo pharmacokinetic properties to the melanoma targeting peptide alone. Moreover, initial clinical trials with C' dots demonstrated they were safe in humans, foreshadowing the translational potential of the DOTA-?MSH-C' dots. Development and optimization of DOTA-?MSH-C' dots will be guided by 3 specific aims. 1) Determine the optimized tunable surface chemistry for melanocortin-1 receptor (MC1-R) targeted silica nanoparticles to achieve favorable cellular binding, uptake, subcellular localization. 2) Evaluate 225Ac- and 177Lu- DOTA-?MSH- C' dot conjugates' in vivo targeting specificities, pharmacokinetics and clearance profiles in B16/F10 syngeneic and M21 human xenografted melanoma tumor bearing mice to determine the lead radiolabeled DOTA-?MSH- C' dot platform. 3) In vivo characterization and safety assessment will be performed with the lead 225Ac and 177Lu labeled DOTA-?MSH conjugates to support an IND application for clinical trials. Therapy studies with the 225Ac and 177Lu labeled DOTA-?MSH-C' dots alone or combined with immunotherapy will be investigated. Malignant melanoma is the most deadly form of skin cancer. It is extraordinarily resistant to chemotherapy, immunotherapy and external beam radiation resulting in low durable response rates. Recently, several new therapeutics were approved for melanoma treatment; however, the responses are usually short-lived (6-12 months) due to drug resistance and activation of alternative signaling pathways. The development of radiolabeled DOTA-?MSH-C' dot nanoparticles is significant since their administration will result in highly localized tumor irradiation with low normal tissue exposure for therapy addressing a critical unmet need for the development of novel efficacious treatments for advanced staged melanoma.